Abstract
Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood tumor whose molecular pathogenesis remains poorly understood. We analyzed a discovery set of 13 CCSKs for changes in chromosome copy number, mutations, rearrangements, global gene expression and global DNA methylation. No recurrent segmental chromosomal copy number changes or somatic variants (single nucleotide or small insertion/deletion) were identified. One tumor with t(10;17)(q22;p13) involving fusion of YHWAE with NUTM2B was identified. Integrated analysis of expression and methylation data identified promoter hypermethylation and low expression of the tumor suppressor gene TCF21 (Pod-1/capsulin/epicardin) in all CCSKs except the case with t(10;17)(q22;p13). TARID, the long noncoding RNA responsible for demethylating TCF21, was virtually undetectable in most CCSKs. TCF21 hypermethylation and decreased TARID expression were validated in an independent set of CCSK tumor samples. The presence of significant hypermethylation of TCF21, a transcription factor known to be active early in renal development, supports the hypothesis that hypermethylation of TCF21 and/or decreased TARID expression lies within the pathogenic pathway of most CCSKs. Future studies are needed to functionally verify a tumorigenic role of TCF21 down-regulation and to tie this to the unique gene expression pattern of CCSK.
Highlights
Clear Cell Sarcoma of the Kidney (CCSK) comprises approximately 5% of all renal malignancies in children, and is observed most often below 3 years of age [1, 2]
SNP arrays and relative coverage generated by whole genome sequencing were used to analyze chromosome segment copy number gain and loss in the 13 paired normal and CCSK tumor samples of the discovery set
Our results suggest that the genome of CCSK is rather stable, similar to the genome of other pediatric tumors occurring at very young age [27]
Summary
Clear Cell Sarcoma of the Kidney (CCSK) comprises approximately 5% of all renal malignancies in children, and is observed most often below 3 years of age [1, 2]. The current intensive treatment schedules for CCSK, including high doses of anthracyclines and radiotherapy, have resulted in a significant improvement in the outcome of these patients with 5-year event-free and overall survivals of approximately 80% and 90%, respectively [2, 4]. Especially in patients with advanced-stage disease and following relapse, outcome is unsatisfactory. The required intensive therapy may result in serious toxicity [5, 6] and treatment options for patients with relapsed CCSK are limited [7, 8]. Prognostic markers that may predict tumor behavior and new molecular targets for therapy are needed
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